genetics of congenital heart disease
TRANSCRIPT
GENETICS OF FAMILIAL CONGENITAL HEART DISEASES
Laxmi Ghimire, MD Clinical Fellow, Pediatric Cardiology UCSF Benioff Children’s Hospital San Francisco, CA
Congenital Heart Diseases
• Congenital heart disease is the leading cause of infant morbidity in the Western world
• Nearly 1% of children have CHD, an additional 1% to 2% of the population harbor more subtle cardiac developmental anomalies. ~10X higher prenatal incidence.
Hoffman. Pediatr Cardiol. 1995.16:155-65.
Congenital Heart Diseases
• Most children born with CHD do not have other birth defects
• CHD occurs in association with other anomalies or as part of an identified syndrome in 25 to 40% cases. ~ 1/3rd of children with a chromosomal abnormality will have CHD.
• Aneuploidy, or abnormal chromosomal number, accounts for a significant proportion of CHD
Bruneau. Nature. 2008 ;451:943-8
What causes CHD ?
• The etiology of CHD is complex and is associated with both environmental and genetic causes.
• Genetically, CHD is a very heterogeneous disease; 55 human disease genes have been identified so far and a lot more in mice.
Multifactorial origin of CHD.
Srivastava et al. Circulation. 2009;120:269-271
Common syndromes resulting from Aneuploidy and microdeletions
Syndrome Cardiac anomalies % with CHD Trisomy 13 ASD, VSD, PDA, HLHS 80%
Trisomy 18 ASD, VSD, PDA, TOF, DORV, CoA, BAV
90-100%
Trisomy 21 ASD, VSD, AVSD, TOF 40-50%
Monosomy X(Turner Syndrome)
CoA, BAV, AS, HLHS 25-35%
47, XXY(Klinefelter Syndrome)
PDA, ASD, mitral valve prolapse
50%
22q11.2 deletion(DiGeorge Syndrome)
IAA type B, aortic arch anomalies, truncus, TOF
75%
7q11.23 deletion(William-Beuren Syndrome)
Supravalvar AS, PPS 50-85%
Garg V. Current Cardiology Reviews, 2010, 6: 91-97
Common Syndromes Associated with CHD Resulting from Single Gene Defects
Syndrome Cardiac anomalies Associated genes Noonan Syndrome PS with dysplastic pulmonary
valve, AVSD, HCM, CoA PTPN11, KRAS, RAF1,
SOS1
Costello Syndrome PS, HCM, cardiac conduction abnormalities
HRAS
LEOPARD Syndrome PS and cardiac conduction abnormalities
PTPN11, RAF1
Alagille Syndrome PS, TOF, ASD, PPS JAG1, NOTCH2
Marfan Syndrome Aortic root dilation and dissection, MVP
FBN1, TGFBR1, TGFBR2
Holt-Oram Syndrome ASD, VSD, AVSD, progressive AV conduction disease
TBX5
Heterotaxy Syndrome DILV, DORV, d-TGA, AVSD ZIC3, CFC1
Char Syndrome PDA TFAP2b
CHARGE Syndrome ASD, VSD, valve defects CHD7, SEMA3E
Garg V. Current Cardiology Reviews, 2010, 6: 91-97
Molecular pathology of congenital heart disease
Cell Mol Life Sci. 2014; 71: 1327–1352.
Genes associated with CHD
CH
D
Genes encoding transcription factors
Genes involved in cell signaling
Genes encoding structural proteins
Genes encoding epigenetic regulators
Non-Syndromic CHD associated with Single Gene Defects
Cardiac anomalies Gene ASD, atrioventricular conduction delay,
TOF, tricuspid valve abnormalities NKX2-5
ASD, VSD GATA4
ASD, hypertrophic cardiomyopathy MYH6
Cardiac septation defects associated with PHTN
BMPR2
Endocardial cushion defects CRELD1, ALK2
BAV, early valve calcification NOTCH1
d-TGA PROSIT-240
Garg V. Current Cardiology Reviews, 2010, 6: 91-97
Danish registry with 1 763 591 persons born in Denmark Included patients from 1977 to 2005 Total of 18 708 had CHD
Risk of Recurrence of CHD by Family History of CHD Among First-Degree Relatives
Heart defect in First-degree relative
Same heart defect phenotype in cohort member
No of CHD Relative risk 95% CI
Heterotaxy 5 79.1 32.9-190
Conotruncal defect 27 11.7 8-17
Septal defects isolated
68 3.41 2.7-4.3
AVSD 8 24.3 12-49
LVOTO 13 12.9 7.5-22
RVOTO 12 48.6 27.5-86
Circulation. 2009;120:295-301
Relative Risk of Recurrence of Any CHD by Family History of CHDs
Any type of CHD in Cohort Member
Family Hx by Kinship type
No. of CHD Relative risk 95% CI
Twin, same sex 169 12.5 10.9-14.3
Twin, unlike sex 46 6.93 5.32-9.04
First-degree relative 549 3.21 2.96-3.49
Second-degree relative
443 1.78 1.09-2.91
Third-degree relative 387 1.10 0.81-1.48
Circulation. 2009;120:295-301
Familial congenital heart disease
• Many congenital heart diseases run in families
• With advances in genetics, we have been able to find the some of the genetic causes of familial congenital heart diseases
• Knowledge of the familial contribution to congenital heart diseases (CHD) on an individual and population level is sparse
Stalmans et al, Nat Med 2003: 173-82
Lambrechts et al. Nat Genet 2003; 34: 383-94.
Familial CHD: Role of VEGF
• Vascular endothelial growth factor (VEGF) – plays critical role in the formation of the endocardial cushions during heart development in mouse model
• Three SNPs in the promoter of VEGF (C2578A, G1154A, and C634G) shown to be a modifier of 22q11 deletion syndrome. Same haplotype was associated with lower VEGF levels in vivo.
• In family based study: the low expression VEGF haplotype was transmitted more often to affected children suggesting that it may play a role in the development of isolated TOF
Stalmans et al, Nat Med 2003: 173-82 Lambrechts et al. Nat Genet 2003; 34: 383-94.
Lambrechts et al. J Med Genet 2005; 42: 519-22
Familial CHD: Role of VEGF
• Newer data: VEGF do not play significant role in CHD
• Genotyped 771 CHD cases, of whom 595 had Tetralogy of Fallot (TOF), and carried out case-control analyses using haplotype-tagging SNPs in VEGF.
• Common or rare genetic variation in VEGF does not significantly predisposes to the risk of TOF
Griffin et al. PLoS One. 2009;4:e4978
MTHFR and CHD
• Initial studies showed strong association between MTHFR and CHD
• Data is all over the place
• A recent very large study: analyzed primary genotyping data on 5814 CHD cases and 10 056 controls, together with meta-analysis of a further 1883 cases and 3103 controls
• They found no significant effect of MTHFR C677T genotype on CHD risk.
Mamasoula et al. Circ Cardiovasc Genet. 2013. 6:347-53
Familial CHD and GATA4
• GATA- family of transcription factors and upstream regulator of genes expressed during embryogenesis and cardiac morphogenesis
• GATA4 and familial TOF
• Three novel heterozygous mutations of GATA4: p.A9P, p.L51V, and p.N285S, were identified in three families with TOF.
• In each family, the mutant allele was present in all the affected family members but absent in unaffected relatives
HumMutat 34:1662–1671, 2013
Familial congenital heart disease
• A family history of any heart defect among first-degree relatives accounts for ~2-5% of the heart defect cases in the population.
• The same heart defect phenotype show strong familial clustering, with relative risks of recurrence of 3-fold to 80-fold in first-degree relatives.
• Few candidate genes have been systematically investigated for any
possible contribution of common variants to disease risk.
• There is limited data, if any, on identification of culprit genes/SNPs through whole genome sequencing on familial congenital heart diseases.
Circulation. 2009;120:295-301